Ageing and neurodegenerative diseases最新文献

Aim: The endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated protein B (VAPB) is implicated in many cellular processes, such as ER-organelle tethering, calcium homeostasis, and unfolded protein response. The P56S missense mutation in VAPB has been associated with familial forms of motor neuron diseases such as typical amyotrophic lateral sclerosis (ALS), atypical ALS, and spinal muscular atrophy. However, it has not been determined how the VAPB P56S mutation induces the degeneration of corticospinal motor neurons (CSMNs) in ALS.

Methods: Using homozygous knock-in (KI) mice expressing P56S VAPB, we investigated the mutation's pathogenic impacts and underlying mechanisms on the survival and function of CSMNs. We performed a wide variety of assays to examine the behavioral, histological, cellular, and molecular abnormalities of KI mice.

Results: Compared with wild-type controls, KI mice showed the downregulated protein level of mutant VAPB, proteinase K-resistant cytoplasmic inclusions of mutant VAPB in CSMNs, abnormal hyperactivity, impaired motor coordination, neuronal loss of CSMNs, and axonal degeneration of pyramidal and corticospinal tracts. Mechanistic studies revealed that the VAPB P56S mutation rendered the mutant protein destabilized and inclusion-prone in cortical neurons, and the proteasomal degradation played a critical role in modulating mutant VAPB's protein level and inclusion formation. In addition, the VAPB P56S mutation disrupted ER-mitochondria contacts, impaired VAPB-PTPIP51 interaction and IP3R-VDAC interaction, elevated cytosolic Ca²⁺, activated CaMKII, and increased CRMP2 phosphorylation. Moreover, the VAPB P56S mutation activated the IRE1-XBP1/p38 mitogen-activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway, increased tau hyperphosphorylation, and upregulated p53 expression and phosphorylation.

Conclusion: These findings demonstrate the progressive degeneration of CSMNs induced by VAPB P56S mutation and indicate the involvement of the Ca²⁺-CaMKII-CRMP2 and IRE1-p38 MAPK/JNK-tau/p53 pathways in the pathogenic process.

Autophagy is a cellular process essential for maintaining neuronal homeostasis by degrading and recycling damaged organelles and proteins. Impairments in canonical autophagy pathways, such as macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy, are linked to Parkinson's disease (PD) pathogenesis, contributing to α-synuclein aggregation and dopaminergic neuronal loss. Moreover, the recent discovery of noncanonical autophagy highlights the unexpected roles of autophagy-related proteins in protein degradation beyond the canonical autophagy pathways. Advances in understanding the molecular mechanisms of autophagy provide potential therapeutic strategies to modulate this pathway in PD. Key therapeutic targets include mTOR and AMPK, with compounds like rapamycin, trehalose, and resveratrol showing promise in preclinical models. Enhancing lysosomal function and mitophagy also presents a viable strategy to alleviate PD symptoms. This review emphasizes the complex roles of autophagy in PD and highlights the potential of autophagy modulation as a promising therapeutic strategy for treating the disease.

Aim: Define the subtype-specific contributions of nigrostriatal dopaminergic neurons (DANs) to motor and non-motor behaviors by comparing Calbindin 1-positive (Calb1 ⁺) and Aldehyde dehydrogenase 1a1-positive (Aldh1a1 ⁺) DANs.

Methods: Intersectional genetic strategy and chemogenetic inhibition were applied to selectively silence Calb1 ⁺ or Aldh1a1 ⁺ DANs in mice. An adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) was stereotactically delivered into the substantia nigra pars compacta of double knock-in lines Th ^Flp; Calb1 ^IRESCre or Th ^Flp; Aldh1a1 ^CreERT2. Following expression, subtype-specific neuronal inhibition was induced with a designer receptor exclusively activated by designer drugs (DREADD) ligand, and the mice were assessed in assays of voluntary movement, motor skill learning, and early associative learning behavior.

Results: Chemogenetic inhibition of either Calb1 ⁺ or Aldh1a1 ⁺ DANs produced a marked reduction in voluntary movement and impaired acquisition of motor skills, indicating that both subtypes are necessary for normal motor function and learning. In contrast, only inhibition of Calb1 ⁺ DANs altered early associative-learning performance, revealing a dissociable, subtype-specific role for Calb1 ⁺ neurons in reinforcement-related behavior that was not observed with Aldh1a1 ⁺ neuron inhibition.

Conclusion: Both Calb1 ⁺ and Aldh1a1 ⁺ nigrostriatal DANs are key regulators of movement and motor learning, with Calb1 ⁺ neurons additionally modulating reward-based associative learning. These findings highlight the functional heterogeneity of nigrostriatal DAN subtypes and identify potential therapeutic targets for addressing motor and non-motor deficits in Parkinson's disease.